The human body has evolved complex mechanisms to perpetuate and protect itself. Sometimes, however, those mechanisms go awry, and either exacerbate or, indeed, cause serious pathologies such as cancer. Despite intensive work and numerous therapeutic advances, a need remains for broadly applicable cancer treatments, especially for tumors that are refractory to current treatments, or become resistant in the course of therapy. Consequently, a continuing need exists for cancer therapies, especially ones that are effective for treating solid tumors and address the drug resistance problem.
Artemisinin-based combination therapies (ACTs) have proven efficacious against multi-drug resistant parasites and are now employed by more than 60 countries following World Health Organization's recommendations. Coartem™ is an example of an ACT indicated for the treatment of acute uncomplicated plasmodium falciparum malaria, the most dangerous form of the disease. It is one of the most successful malaria treatments of its kind, being a highly effective and well-tolerated treatment. It provides cure rates of up to 97%, even in areas of multi-drug resistance.
Coartem has two active pharmaceutical ingredients; a derivative of artemisinin called artemether and lumefantrine (aka benflumetol) an antimalarial drug. This combination of ingredients is discussed in U.S. Pat. No. 5,677,331 issued Oct. 14, 1997. The composition can be formulated into solid dosage forms such as tablets and is useful for the treatment of drug-resistant malaria. The use of lumefantrine for constructing synergistic antimalarial compositions is also described in U.S. Pat. No. 5,637,594 issued Jun. 10, 1997.
Lumefantrine (IUPAC name: 2-(dibutylamino)-1-[(9E)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl]ethanol, CAS number: 82186-77-4) is an aminoalcohol which exists as a 1:1 racemic mixture of dextrorotatory and levorotatory enantiomers.
Several other compounds have been used as alternatives to lumefantrine in formulating ACTs for treating malaria. Examples of these compounds are discussed in the U.S. Pat. No. 5,637,594. These include halofantrine, amodiaquine, quinine, mefloquine, chloroquine, pamaquine, primaquine, tafenoquine, quinacrine, mepacrine and pyronaridine. Piperaquine is part of ACT therapy known as (Duo-Cotecxin™). Napthoquine has been clinically evaluated as component in an ACT.
A leading model of ACT anti-plasmodial activity hypothesizes that iron-mediated cleavage of the endoperoxide bridge within the artemisinin compound generates cytotoxic drug metabolites capable of damaging cellular macromolecules. In the parasite digestive food vacuole, neutral lipids are closely associated with heme and promote hemozoin formation. It is likely that artemisinin and its derivatives are activated by heme-iron within neutral lipid environment of the food vacuole. In mammalian cells the analogous digestive compartment to food vacuoles is the lysosome.